Signal Transducer and Activator of Transcription 3 (STAT3) is a signal transducer and activator of transcription that transmits signals from cell surface receptors to the nucleus. STAT3 is frequently hyperactivated in many human cancers. Under normal conditions, STAT3 activation is transient and tightly regulated. Upon cellular stimulation by ligands such as growth factors or cytokines, STAT3 become phosphorylated on critical tyrosine residue (Tyr705) and consequently induce STAT3 dimerization through two reciprocal phosphotyrosine (pTyr)-Src-homology 2 (SH2) interactions. The STAT3 dimers then translocate to the nucleus and bind to specific DNA-response elements in the promoters of target genes thereby activating transcription. The association of aberrant STAT3 activation with many types of human malignancies and solid tumors has made STAT3 an attractive molecular target for the development of novel cancer therapeutics. (See Darnell, Science 1997; 277:630-1635; Darnell, Nat. Med. 2005; 11:595-596; Bromberg, Oncogene 2000; 19:2468-2473; Yu, Nat. Rev. Cancer 2004; 4:97-105; Bowman, Oncogene 2000; 19:2474-2488; Yue, Expert Opin. Inv. Drug 2009; 18:45-56.)
STAT3 is found to be constitutively activated in tumor cells and contribute to tumor progression through the modulation of some target genes, such as antiapoptotic genes Bcl-xL, Bcl-2, Mcl-1 and survivin along with genes driving cell cycle progression, c-Myc and cyclin-D1. (Id.; Buettner, Clin. Cancer Res. 2002; 8:945-954.) Aberrant activation of STAT3 is most frequent in almost all blood malignancies and solid tumors, including lymphoma and leukemia, breast, prostate, lung head and neck, brain and colon cancer. (See Turkson, Expert Opin. Ther. Tar. 2004; 8:409-422. Burke, et al., Oncogene 2001; 20:7925-7934; Berishaj, et al., Breast Cancer Res 2007; 9:R32; Barton, et al., Mol. Cancer Ther. 2004; 3:11-20; Krueger, et al., Oncogene 1991: 6; 245-56; Chaturvedi, Mol. Cell. Biol. 1997; 17:3295-3304; Song, Oncogene 2000; 19:2489-2495.) These features have made STAT3 an attractive target for the development of anticancer agents.
The design of compounds that target STAT3 has been the subject of several recent reviews. (See Mankan, et al., Expert Opin. Inv. Drug 2011; 20:1263-1275; Lavecchia, et al., Curr. Med. Chem. 2011; 18:2359-2375; Yap, Med. Chem. Comm 2012; 3:541-551; Masciocchi, et al., Future Medicinal Chemistry 2011; 3:567-597; Zhao, et al., Curr. Med. Chem. 2011, 18, 4012-4018.) The direct targeting of STAT3 is a particularly attractive way to inhibit its function. Several approaches have been taken to inhibit the dimerization of phosphorylated STAT3 by blocking the SH2 domain binding site of the phosphorylated STAT3 tyrosine-705 residue. The first inhibitors of STAT3 dimerization were peptides and phosphopeptides (Turkson, et al., J. Biol. Chem. 2001; 276:45443-45455; Coleman, et al., J. Med. Chem. 2005; 48:6661-6670). Significant advances have been made by the groups of McMurray (Mandal, et al., J. Med. Chem. 2011; 54:3549-3563; Mandal, et al., J. Med. Chem. 2009; 52:2429-2442; Mandal, et al., J. Med. Chem. 2009; 52:6126-6141) and Wang (Chen, et al., ACS Med Chem. Lett. 2010; 1:85-89) by using structure-based approaches resulting in potent peptide-like inhibitors incorporating a phosphotyrosine residue. These potent cell permeable STAT3 dimerization inhibitors have considerable ADME liabilities since the high affinity SH2 domain binding derives, at least in part, from the necessary presence of a hydrolyzable phosphate group.
As an alternative approach considerable attention has been paid to the discovery of non-peptidic small molecule drug-like inhibitors of STAT3 dimerization to avoid some of the ADME challenges inherent in the development of peptide-like inhibitors. (See Fletcher, et al., Chem. Bio. Chem. 2009; 10:1959-1964; Hao, et al., Bioorg. Med. Chem. Lett. 2008; 18:4988-4992; Matsuno, et al., ACS Med Chem. Lett. 2010; 1:371-375; Ren, et al., ACS Med. Chem. Lett. 2010; 1:454-459; Schust et al., Chem. Biol. 2006; 13:1235-1242; Shahani, et al., ACS Med Chem. Lett. 2011; 2:79-84; Siddiquee, et al., ACS Chem. Biol. 2007; 2:787-798; Song, et al., P. Natl. Acad. Sci. USA 2005; 102:4700-4705; Uehara, et al., Biochem. Biophys. Res. Commun. 2009; 380:627-631.) What are needed are new STAT3 inhibitors and methods of making and using same. The compounds, compositions, and methods disclosed herein address these and other needs.